Phospholipase A2(PLA2) in general is an enzyme which specifically hydrolyzes the ester bonds at the sn-2 position of glycerophospholipids and produces fatty acids and lysophospholipids. At the present time, in mammals, the existence 10 types or more of PLA2 has been found. They are classified based on their locality, molecular weight, substrate specificity, etc. to secretory type PLA2 (sPLA2), cytosolic PLA2 (cPLA2), Ca2+ independent PLA2 (iPLA2) and other families, but among these, cPLA2 plays a central role in the stimuli-induced production of lipid mediators, since it selectively releases arachidonic acid from the sn-2 position of the glycerophospholipids in the cytoplasm, adjusts the activity in the presence of a μM concentration of calcium ions or by phosphorylation by mitogen-activated protein kinase (MAP kinase).
It is known that arachidonic acid taken from PLA2 produces as metabolites prostanoids, leukotrienes, platelet activating factors and other lipid mediators having various bioactivities.
The action of cyclooxygenase (COX) on arachidonic acid produces prostanoids. “Prostanoids” is the general name for prostaglandins (PG) and thromboxanes (TX). Prostaglandins include prostaglandin E2 (PGE2), prostaglandin D2 (PGD2), prostaglandin F2α (PGF2α), prostaglandin I2 (PGI2), etc., while thromboxanes include thromboxane A2 (TXA2), thromboxane B2 (TXB2), etc. These prostanoids express various physiological actions through specific receptors.
5-lipoxygenase (5-LOX) acts on arachidonic acid to produce leukotrienes (LT). Leukotrienes include leukotriene B4 (LTB4), cysteinyl leukotriene (Cys-LT), etc. Cysteinyl leukotriene includes leukotriene C4 (LTC4), leukotriene D4 (LTD4), leukotriene E4 (LTE4), etc.
On the other hand, when the phospholipids of membranes are hydrolyzed by cPLA2 and arachidonic acid is released, lysophospholipids are produced. Lysophospholipids are metabolized and produce platelet activating factors (PAF). It is known that the prostanoids produced from the COX route have various physiological activities and are involved in the conditions of various diseases.
It is known that PGE2 has a fever-inducing action, pain increasing action, vasodilating action and other inflammatory actions. COX inhibitors are widely used as anti-inflammatory drugs and analgesics in inflammatory diseases such as rheumatoid arthritis, osteoarthritis or other arthritis. It is clear that PGE2 is involved in swelling and pain or other conditions in inflammatory diseases (See Non-Patent Document 1).
It is known that PGD2 has an airway smooth muscle contraction action, increased vascular permeability action, eosinophil chemotactic action, and other actions. In recent years, in studies of the DP receptor, that is a receptor of PGD2, deficient mice it has been clarified that the allergic airway inflammation is remarkably ameliorated, the production of Th2 type cytokine is decreased at the airway inflammation site, etc., and therefore, the possibility of PGD2, which is deeply involved in conditions of allergic airway inflammation including bronchial asthma through actions through its receptor (DP receptor), is suggested (See Non-Patent Document 2).
Further, DP receptor selective inhibitors suppress the airway inflammation and development of airway hyperreactivity in animal models of asthma (See Non-Patent Document 27).
PGE2 and PGD2 are induced, depending upon the inflammation of the allergic colitis induced by food and COX inhibitors exhibit a suppressive action, so it is clear that PGE2 and PGD2 are involved in food allergy and allergic colitis conditions (See Non-Patent Documents 29 and 30).
TXA2 and TXB2 have a platelet aggregation action, vascular smooth muscle contraction action, airway smooth muscle contraction action and other actions. TX synthesizing enzyme inhibitors and TXA2 receptor antagonists suppress the development of airway hyperreactivity and asthmatic broncoconstrictions, and therefore, are used as drugs for treatment of asthma. It is shown that TXA2 and TXB2 contribute to conditions of bronchial asthma or other respiratory diseases (See Non-Patent Document 3).
It is known that the LT produced from the 5-LOX pathway also has various physiological activities and is involved in conditions of various diseases. LTB4 is a powerful activating factor of white blood cells, promotes the exuding of neutrophils or other inflammatory cells to the inflammatory site and stimulates the release of superoxides and proteases damaging the tissue. In recent years, in mice deficient in the BLT1 receptor, a receptor of LTB4, alleviation of allergic airway inflammation and airway hyperreactivity and suppression of the Th2 type immunoreaction have been reported, so the involvement of LTB4 in bronchial asthma or other airway inflammatory conditions is suggested (See Non-Patent Document 4).
Further, Cys-LT (LTC4/LTD4/LTE4) exhibits a bronchial smooth muscle contraction action and action in chemoattracting and activating eosinophils and other inflammatory cells. The Cys-LT1 receptor, a receptor of Cys-LT, antagonist exhibits efficacy in an animal asthma model. Further, in clinical studies as well, its pharmaceutical effect as a drug for treatment of bronchial asthma and allergic rhinitis has been confirmed, and therefore, it is known that Cys-LT is deeply involved in allergic airway inflammation (See Non-Patent Document 5). The PAF produced by metabolization of lysophospholipids exhibits a platelet activating action, bronchial smooth muscle contraction action and other physiological actions. From studies using PAF receptor deficient mice, the involvement of PAF in exacerbation of bronchial asthma, multiple sclerosis, osteoporosis, acute lung injury or other conditions has been suggested (See Non-Patent Documents 6, 7, 8 and 9).
Further, it is shown that a PAF receptor antagonist ameliorates airway hyperreactivity in bronchial asthma patients (See Non-Patent Document 28).
As described above, cPLA2 is a major enzyme which acts on the phospholipids of the cell membrane and produces arachidonic acid and lysophospholipids, and therefore, plays an important role in the production of prostanoids, LT, PAF, and other lipid mediators. Therefore, if inhibiting the cPLA2 enzyme so as to suppress the release of arachidonic acid and lysophospholipids, the production of prostanoids, LT, PAF and other lipid mediators positioned downstream of the metabolic cascade should be suppressed and, in turn, it is believed that treatment or prevention of various diseases initiated or exacerbated by production of these lipid mediators should become possible. As examples of such diseases, rheumatoid arthritis, osteoarthritis, dysmenorrhea, acute pain, bronchial asthma and other asthma, allergic rhinitis, chronic and acute airway inflammation, chronic obstructive pulmonary disease, acute lung injury, multiple sclerosis, cerebral ischemia/reperfusion injury, dermatitis, ulticaria, eczema, prurigo, pancreatitis, psoriasis, inflammatory colitis, food allergy, allergic colitis, osteoporosis, atherosclerosis, etc. may be mentioned.
Up to now, it has been reported that several types of cPLA2 inhibitor exhibit efficacy in animal models such as asthma, acute lung injury, cerebral ischemia/reperfusion injury, arthritis, dermatitis and other animal models (See Non-Patent Documents 10, 11, 12, 13 and 14). Further, in cPLA2α-deficient mice, alleviation of the disease is observed in asthma, arthritis, acute lung injury, pulmonary fibrosis, inflammatory bone resorption, multiple sclerosis, cerebral ischemia/reperfusion injury, atherosclerosis, and other models (See Non-Patent Documents 15 and 31). In these diseases, it is believed that cPLA2 is involved in the onset or exacerbation of the disease, and therefore, inhibiting the cPLA2 should enable treatment or prevention of these diseases.
cPLA2 inhibitors have already been described in reviews (See Non-Patent Documents 16 and 17), and as described above, some of the inhibitors has been reported to have the efficacy in animal disease models. Further, recently, in addition to the cPLA2 inhibitors described in the reviews referenced above, oxa(thia)zolidine derivatives (See Patent Documents 1 and 2), oxadiazolidinedione derivatives (See Non-Patent Document 18), triazinetrione derivatives (See Non-Patent Document 18), oxamide derivatives (See Non-Patent Documents 19 and 20), trifluorobutanone derivatives (See Patent Document 3 and Non-Patent Document 13), propanone derivatives (See Non-Patent Document 21), indolylpropanone derivatives (See Non-Patent Document 22), indole derivatives (See Patent Document 4 and Non-Patent Document 23), etc. are disclosed as novel cPLA2 inhibitors. However, there has been no example of the above cPLA2 inhibitors being commercialized as pharmaceuticals.
On the other hand, indole skeleton compounds similar, in structure, to the present invention compounds have been disclosed in the documents (See Patent Documents 5 and 6 and Non-Patent Document 24) etc., but there is no description of the compounds having an aromatic group directly at the nitrogen atom of 1-position as disclosed in the present invention and no disclosure relating to the cPLA2 inhibiting activity.
Further, indole skeleton compounds similar in structure to the present invention compounds are disclosed in the documents (See Patent Document 7), but the substituents of the indole at 2-position and 3-position differ from the present invention. Further, the document does not relate to a pharmaceutical. Further, the documents (See Non-Patent Documents 25 and 26) etc. concerning the examples of production of indole skeleton compounds are known, but the substituents of the compounds differ from the present invention compounds.    Patent Document 1: WO 03/000668    Patent Document 2: WO 01/072723    Patent Document 3: WO 99/015129    Patent Document 4: WO 03/048122    Patent Document 5: WO 05/016339    Patent Document 6: U.S. Pat. No. 5,994,554    Patent Document 7: EP 1526159    Non-Patent Document 1: Nippon Yakuriǵaku Zasshi 118 (2001) 219    Non-Patent Document 2: Molecular Medicine 42 (2005) 1137    Non-Patent Document 3: Eur J Pharmacol 533 (2006) 89    Non-Patent Document 4: J Immunol 175 (2005) 4217    Non-Patent Document 5: Nippon Yakurigaku Zasshi 120 (2002) 343    Non-Patent Document 6: J Immunol 172 (2004) 7095    Non-Patent Document 7: J Exp Med 202 (2005) 853    Non-Patent Document 8: J Clin Invest 114 (2004) 85    Non-Patent Document 9: J Clin Invest 104 (1999) 1071    Non-Patent Document 10: Eur J Pharmacol 539 (2006) 195    Non-Patent Document 11: Am J Physiol Lung Cell Mol Physiol 284 (2003) L720    Non-Patent Document 12: Transplantation 81 (2006) 1700    Non-Patent Document 13: J Pharmacol Exp Ther 298 (2001) 376    Non-Patent Document 14: Eur J Pharmacol 326 (1997) 237    Non-Patent Document 15: IUBMB Life 58 (2006) 328    Non-Patent Document 16: Drugs Fut 25 (2000) 823    Non-Patent Document 17: Expert Opin Ther Patents 11 (2001) 1123    Non-Patent Document 18: Bioorg Med Chem Lett 16 (2006) 2978    Non-Patent Document 19: J Med Chem 45 (2002) 2891    Non-Patent Document 20: J Med Chem 49 (2006) 2821    Non-Patent Document 21: J Med Chem 45 (2002) 1348    Non-Patent Document 22: J Med Chem 49 (2006) 2611    Non-Patent Document 23: J Med Chem 49 (2006) 135    Non-Patent Document 24: Bioorg Med Chem Lett 9 (1999) 3329    Non-Patent Document 25: J Org Chem 64 (1999) 5575    Non-Patent Document 26: Org Lett 2 (2000) 1403    Non-Patent Document 27: J Pharmacol Exp Ther 298 (2001) 411    Non-Patent Document 28: Am J Respir Clit Care Med 152 (1995) 1198    Non-Patent Document 29: Aliment Pharmacol Ther 8 (1994) 301    Non-Patent Document 30: Gut 45 (1999) 553    Non-Patent Document 31: Biol Pharm Bull 31 (2008) 363